Pericentromeric Satellite III transcripts induce etoposide resistance

Julian Kanne, Michelle Hussong, Jörg Isensee, Álvaro Muñoz-López, Jan Wolffgramm, Felix Heß, Christina Grimm, Sergey Bessonov, Lydia Meder, Jie Wang, H. Christian Reinhardt, Margarete Odenthal (+4 others)
2021 Cell Death and Disease  
AbstractNon-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized
more » ... hat the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.
doi:10.1038/s41419-021-03810-9 pmid:34031359 fatcat:rqvslwkjpngufdpt33nr3hskpi